1-(p-chloro-m-nitrophenyl-diphenylmethyl)-imidazole as an antifungal agent

ABSTRACT

N-TRITRYL-IMIDAZOLES AND SALTS THEREOF THE FORMULA:   1-(((X)N-PHENYL-)((X&#39;&#39;)N&#39;&#39;-PHENYL)((X&#34;)N&#34;-PHENYL)-C-),2-R,   4-R1,5-R2-IMIDAZOLE   WHEREIN R, R1 AND R2 ARE HYDROGEN, LOWER ALKYL OF PHENYL, OR R1 AND R2 TOGETHER FORM AN ANELLATED BENZENE RING, X, X&#39;&#39; AND X&#39;&#39;&#34; ARE ALKYL OF 1 TO 12 CARBON ATOMS OR AN ELECTRO-NETATIVE MOIETY, AND N N&#39;&#39; AND N&#34; ARE AN INTEGER FROM 0 TO 2, OR PHARMACEUTICALLY ACCEPTABLE ACID SALTS THEREOF MAY BE PRODUCED BY REACTING A SILVER SALT OF ALKALI METAL SALT OF AN IMIDAZOLE OF THE FORMULA:   2-R,4-R1,5-R2-IMIDAZOLE   WITH A TRITYL HALIDE OF THE FORMULA:   ((X)N-PHENYL)((X&#39;&#39;)N&#39;&#39;-PHENYL)((X&#34;)N&#34;-PHENYL)-C-HAL   WHEREIN THE SUBSTITUENTS ARE AS BORE DEFINED AND HAL IS HALOGEN. THESE COMPONENTS ARE USEFUL AS ANTIMYCOTICS.

United States Patent Int. Cl. A61k 27/00 US. Cl. 424-273 2 ClaimsABSTRACT OF THE DISCLOSURE N-trityl-imidazoles and salts thereof of theformula:

wherein R, R and R are hydrogen, lower alkyl or phenyl, or R and Rtogether form an anellated benzene ring, X, X and X" are alkyl of l to12 carbon atoms or an electro-negative moiety, and n, n' and n are aninteger from 0 to 2,

or pharmaceutically acceptable acid salts thereof may be produced byreacting a silver salt or alkali metal salt of an imidazole of theformula:

N N H with a trityl halide of the formula:

Xn Hal Xx.

XIIn wherein the substituents are as above defined and Hal is halogen.These compounds are useful as antimycotics.

This application is a division of US. Ser. No. 758,594, filed Sept. 9,1968, now US. Pat. No. 3,660,577.

The present invention is concerned with N-tritylimidazoles and saltsthereof and the production of such compounds. More particularly, thepresent invention is 3,720,770 Patented Mar. 13, 1973 concerned withN-trityl-imidazoles and salts thereof of the formula:

-N Ra 1.

XII

wherein or pharmaceutically acceptable acid salts thereof. When R, R orR are alkyl moieties, those having 1 to 4 carbon atoms are preferred.When X, X' or X" is an alkyl moiety, it is preferred that such have 1 to12 carbon atoms and such moieties having 1 to 4 carbon atoms areespecially preferred. Electro-negative substituents which areparticularly preferred are the halogens, i.e., fluorine, chlorine,bromine and iodine, N0 CF CN, as well as S-lower alkyl and -0-loweralkyl; it is preferred that the alkyl moieties have 1 to 4 carbon atoms.The term alky and lower alky comprises straight chain as well asbranched chain alkyl moieties and also include those containing a doublebond.

The salts of the N-trityl-imidazoles (I) are the pharmaceuticallyacceptable non-toxic acid salts. Examples of suitable acids are thehydrohalic acids (hydrochloric being particularly preferred), phosphoricacid, monoand bifunctional carboxylic acids, such as acetic acid,propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid,citric acid, salicylic acid, sorbic acid, lactic acid and 1,5-naphthalene-disulphonic acid. The hydrohalides, especially thehydrochlorides, lactates and salicylates are of particular value.

In a particularly preferred embodiment of the present invention, theN-trityl-imidazoles have the formula:

Xn I X (II) (Ila) wherein X, X and X" are alkyl of 1 to 12 carbon atomsor electro-negative substituents and n, n and n" are 1 or 2. With regardto Formula Ila, particularly preferred substituent values are thosewhere X" is fluorine, chlorine, bromine, iodine, N0 CF CN, SCH OCH andn" is 1.

The compounds of the present invention can be prepared according totechniques per se known, such as by reacting silver salts or alkalimetal salts, in particular the potassium salts of imidazoles of theFormula III with trityl halides of the Formula IV:

R, R and R X, X' and X" and n, n and n have the above meanings and Halis chlorine, bromine or iodine, in an inert solvent such as benzene,toluene, hexane, cyclohexane or diethyl ether, at a temperature of fromabout 20 C. to about 110 C. [cf. Chem. Ber. 92, 92 (1959); 93, 570(1960)].

The compounds of the present invention can also be prepared according totechniques per se known by reacting imidazole derivatives of the FormulaIII with tritylcarbinols (cf. the reaction of the carbinol correspondingto the halide IV with secondary amines). In this case, the imidazole isgenerally used in an excess of up to about 100%. If the process iscarried out under pressure, molar amounts may be used. Furthermore, itmay be expedient to carry out the elimination of water azeotropically inthe presence of a high boiling inert organic solvent, such as xylene,chlorobenzenes and the like, at the boiling point of the solvent used.In the absence of solvents, the process is carried out at a temperaturerange of from about 140 C. to about 230 C. and preferably from about 170C. to about 190 C.

It may further be expedient to facilitate the elimination of water byworking in the presence of dehydrating agents, such as e.g. alkalineearth metal oxides (MgO BaO, CaO) and of A1 approximately molar amountsbeing generally used, but possibly also an excess of up to about 2-3moles.

The following table gives the constants of some N- trityl-imidazoles (I,II by way of example:

M.P.: C. (a) 1-(trisphenyl-methyl)-imidazole 226-227 (b)1-(trisphenyl-methyl)-2-methyl-imidazole 225 (c)l-(trisphenyl-methyl)-2,4-dimethyl-imidazole 232 (d) 1 (trisphenylmethyl)-4,5-diphenyl-imidazole 228-230 (e) 1 (p chlorophenyl diphenylmethyl)-imidazole 140 (f) 1 (p fluorophenyl diphenyl methyl)imidazole145 (g) 1-(p-tolyl-diphenyl-methyl)-imidazole 128 (h) l-(trisphenyl-methyl )-benzimidazole 180-181 (1) 1(o-chlorophenyl-diphenyl-methyl)-imidazole 147-149 (i) 1 (m chlorophenyldiphenyl-methyl)-imidazole 114 (k) 1 (p bromophenyl diphenylmethyl)-imidazole 152 (l) 1 (o fluorophenyl diphenyl-methyl)-imidazole185 (In) 1 (m fluorophenyl diphenyl methyl)-imidazole 174 (n) 1 (pnitrophenyl-diphenyl-methyl-imidazole 160-170 (0) 1 (mtrifluoromethylphenyl diphenyl-methyl)-imidazole 156 (p) 1 (pcyanophenyl diphenyl-methyl)-imidazole 164 (q) 1 (o methoxyphenyldiphenyl-methyl)-imidazole 130 (r) 1 (p methylthiophenyl diphenylmethyl) 4 (s) 1 (p fluorophenyl-diphenyl-methyl)-2-rnethyl- (x) 1 (mcyanophenyl diphenyl methyl)-imidazole 119 (y) 1 (o cyanophenyl diphenylmethyl) imidazole 149-151 EXAMPLE OF PREPARATION1-[p-chlorophenyl-diphenyl-methyl]-imidazole (e) 1 molep-chlorophenyl-diphenyl-methyl-carbinol is mixed with about 2 molesimidazole and the mixture is heated without a solvent, at about 180 C.for 5 hours. After cooling, the reaction product is reprecipitated fromxylene in order to remove the excess imidazole. After anotherreprecipitation from benzene light petrol, the pure1-[p-chlorophenyl-diphenyl-methyl]-imidazole is obtained. M.P. -143 C.;yield 53% of theory.

The same compound can also be obtained, when finely powdered silver saltof imidazole is suspended with the equimolar amount ofp-chlorophenyl-diphenyl-methyl chloride in absolute benzene, the mixtureis heated with stirring and with the exclusion of light at boilingtemperature for about 3 hours, the precipitated silver chloride issubsequently filtered off and the residue remaining after removal of thesolvent is recrystallised from benzene/ light petrol.

By analogous procedure, l-(tris-phenyl-methyl)-imidazole is producedfrom 1-tris-phenyl-methyl-carbinol and imidazole andl-(p-tolyl-diphenyl)-imidaz0le is produced from1-p-tolyl-diphenyl-methyl-carbinol and imidazole.

The other compounds (I, II) can also be obtained according to the aboveprocesses. The conversion of the free compounds into the salts islikewise carried out in known manner.

SALTS OF TRITYL-IMIDAZOLIES N-triphenyl-methyl-imidazolium lactate 31 g.N-trityl-imidazole are dissolved by heating in acetonitrile and 10 g.(0.11 mole) d,l-lactic acid are subsequently added. The residueremaining after distilling off the solvent is caused to crystallise bycovering it with ether, the crystallisation product is washed with etherand dried. Yield 40 g. of a colourless crystalline powder of M.P.170-180 C.

N-triphenyl-methyl-imidazolium chloride 31 g. N-trityl-imidazole aredissolved in 400 ml. carbon tetrachloride, and hydrogen chloride issubsequently passed into the solution at room temperature. Thehydrochloride is precipitated after some time and filtered oft withsuction. Colourless crystals of M.P. C. after recrystallization fromacetone/ether 1:1. Yield 33 g.

The following salts are obtained in an analogous manner:

1 (p-chlorophenyl-diphenyl-methyl)-imidazohum-chloride 128-30 1(p-chlorophenyl-diphenyl-methyl)-imidazolium-lactate 90 1(p-chlorophenyl-diphenyl-methyl)-imidazolium-salicylate--oil 1(m-chlorophenyl-diphenyl-methyl)-imidazolium-hypochloride 153 1(o-chlorophenyl-diphenyl-methyl)-imidazolium-chloride 159 1(p-fiuorophenyl-diphenyl-methyl)-imidazolium-chloride 1 1(p-fiuorophenyl-diphenyl-methyl)imidazolium-lactate 95 1(p-fiuorophenyl-diphenyl-methyl)-imidazo lium-lactate 1 10 1(m-fluorophenyl-diphenyl-methyl)-imidazoliumlactate 120 1(p-fiuorophenyl-diphenyl-methyl)-imidazolium-salicylate 80 1(p-cyanophenyl-diphenyl-methyl)-imidazolium-chloride 147 1(o-cyanophenyl-diphenyl-methyl)-imidazolium-chloride 13 l 1(p-cyanophenyl-diphenyl-methyl)-imidazolium-lactate 90 The previouslyknown antimycotics are effective either only against yeasts, such ase.g. Amphotericin B, or only against hyphomycetes, such as e.g.Griseofulvin.

In contrast thereto and surprisingly, the compounds (I, II) and theirsalts are effective against hyphomycetes as well as against yeasts, evenin the case of oral administration. It is another advantage that thecompounds according to the invention are well tolerated by warm-bloodedanimals.

The compounds can 'be used as antimycotics, inter alia, in the form ofan aqueous emulsion, suspension or solution which can be administeredper os. It is also possible to use aqueous solutions of the new salts ofthe said compounds (I).

THERAPEUTIC EFFECT 1) In vitro-effect against human-pathogenic fungi (a)Candida albicans:

Fungistatic: 'y/ml. Compound (a) 40 Compound (e) 4 Compound (f) 4Compound (g) 4 Compound (i) 4 Compound (p) 4 (b) T richophytonmentagrophytes: 4-l0'y fungistatic microsp. fel. 4

The test medium was Milieu de'preuve according to Sabouraud.

The spectrum of activity and the intensity of activity (Compound I) (in-vitro) can be seen from the following table:

MINIMUM INHIBITING CONCENTRATION AS 'y/ML.

Without With serum serum asteroides crateriforme equinum (NL) cgutnum,woolly (Hoechst) equmum, gran. (Hoechst)- tonsurum Trich. megm'm'i...Trich. mentagrophytes Trish. rubrum Microsp. audouinii Microsp. canis(NL) Microsp. cams (our isolatio Microsp. duboisii Microsp. fulvum (18)Microsp. galltnac Microsp. felineum (20) Aspergillus mg (21) Pm.c0mune.. (22) Mucor mucodo. (23) Blakeslca trispora (24) Cami. albz'ctms1 Fungistase.

(2) Effect in vivo (a) Experimental candidosis in white mice.-In thecase of oral administration, curative effects can be achieved with dailydoses of 2-3 times 0.5-1 mg./mouse/ day.

(b) Experimental trychophytia in mice caused by T rich. quinckeanum.-Development of the infection is prevented by daily doses of 1-2 times 1-2mg./mouse orally.

(0) Experimental trichophytia in guinea pigs caused by Trich.ment.When15-30 mg. are administered twice per os to guinea pigs weighing 400grams, a reproducible efiect on the course of the infection and rapidhealing of the mycotic lesions is found.

Equally effective results are produced when other compounds within thescope of (I) or salts of compounds within the scope of (I) andspecifically salts of compounds (a), (e), (f), (g), (i) and (P) areused. Compounds which are unsubstituted in the imidazole ring may besubstituted in one phenyl group by a halogen atom, preferably chlorineor fluorine in the 0-, mor p-position; such compounds and their saltswith hydrochloric acid, lactic acid or salicylic acid are particularlyuseful. The following usages and dosage ranges are used for thecompounds of the present invention:

(a For use with humans:

(1) Dermatomycoses, caused by fungi of the species Trychophytes,Microsporium, Epidermophytes, Aspergillus, Candida albz'cans and otheryeasts;

(2) Organomycoses caused by yeasts, mould fungi and dermatophytes;

(b) For veterinary use: Dermatomycoses and organomycoses caused byyeasts, mould fungi and dermatophytes.

The compounds of the present invention are administered orally orparenterally as well as locally in the form of solutions, e.g., alcohol,preferably ethanol and isopropanol, buffer solutions, powders, tablets.

The dosage range for humans is in the range of from about 20 to aboutmg./kg. and preferably from about 40 to about 60 mg./ kg. Administrationis generally recommended at intervals of about 12 hours and suchadministration should be continued for from about 10 to about 60 days.

Nevertheless it may sometimes be necessary to digress from the aforesaidamounts, dependent on the method of administration or also on account ofindividual reactions to the medicine or on the type of its formulationand the moment in time or the intervals at which it is administered. Insome cases, it may be sufficient to use less than the minimum amountstated above, whereas in other cases it may be necessary to go beyondthe stated upper limit. If larger amounts are applied, it may beadvisable to distribute these over a day in several individual doses.

The compounds of the present invention can be used either as such or incombination with pharmaceutically acceptable carriers. Suitable formsfor administration in combination with various inert carriers aretablets, capsules, powders, sprays, aqueous suspensions, injectablesolutions, elixirs, syrups and the like. Carriers of this type comprisesolid extenders or fillers, a sterile aqueous medium as well as variousnon-toxic organic solvents and the like. Obviously, the tablets and thelike suitable for oral administration can be provided with an additionof saccharin or a similar additive. In the aforesaid case, thetherapeutically active compound should be present in the total mixtureat a concentration of about 0.5 to 90 percent by weight, i.e., inquantities which suffice to attain the range of dosage mentioned above.

In the case of oral administration, obviously, tablets may also containadditives such as sodium citrate, calcium carbonate and dicalciumphosphate together with various additives such as starch, preferablypotato starch and the like, and binders such as polyvinyl-pyrrolidone,gelatin and the like. It is further possible to add lubricants such asmagnesium stearate, sodium lauryl-sulphate and talc for producingtablets. In the case of aqueous suspensions and/or elixirs which areintended for oral administration, the active ingredient may be usedtogether with various agents for improving the flavor, dyestuffs,emulsifiers and/or diluents, such as water, ethanol, ropylene-glycol,glycerol and other compounds or combinations of this type.

In the case of parenteral administration, there may be used solutions ofthe active ingredients in sesame or peanut oil or in aqueouspropylene-glycol of N,N-dimethyl formamide, as well as sterile aqueoussolutions if the compounds are water-soluble. Such aqueous solutionshould be buffered in the usual manner, if required, and the liquiddiluent should previously be rendered isotonic by the addition of thenecessary amount of salt or glucose. These aqueous solutions areparticularly suitable for intravenous, intramuscular and intraperitonealinjections.

In humans, a dosage of 40 mg./kg. administered at intervals of 12 hoursresult in a blood level of between and 11 'y/ml. The half-life period inhuman serum in vivo amounts to 6 hours on the average. Up to 30 to 40%of the administered amount of the substance are excreted with the urinein active form. The resorption quota amounts to more than in the case oforal administration.

The LD for mice, rats, rabbits, dogs and cats lies between about 600 and2200 mg. of the stated compounds/kg. body weight in the case of oraladministration.

The present invention also includes pharmaceutical compositionscomprising at least one of the N-tritylimidazoles or salts thereof inadmixture with a solid or liquid diluent or carrier which maybe any ofthe conventional diluents or carriers used in pharamaceuticalcompositions.

The present invention also includes unit dosage forms of medicationwhich comprise at least one of the compound of the present inventioneither alone or in admixture with a solid or liquid diluent or carrier.The compounds of the present application may include a protectiveenvelope or cover containing the active compound within. Unit dosageform means that the composition is in the form of discrete portions,each containing a unit dose or a multiple or sub-multiple of the unitdose of the active ingredient which is the compound of the presentinvention. Such portions may, for example, be in monolithic coherentform, such as as tablets, suppositories, pills or drages; in wrapped orconcealed form, such as wrapped powders, cachets, sachets or capsules,in ampules such as in sterile solution; or in other forms known to theart.

What is claimed is:

1. An antifungal composition for administration to humans and animalswhich comprises an amount of the compound 1-(p-chloro-m-nitrophenyl-diphenyl-methyl imidazole, or a pharmaceuticallyacceptable non-toxic salt thereof, sufiicient to be therapeuticallyeffective against fungi pathogenic to humans and animals, in combinationwith a pharmaceutically acceptable non-toxic inert diluent or carrier.

2. A method of treating fungal infections in humans and animals, whichcomprises administering to a human or animal so-afilicted an amountsufficient to be therapeutically effective against said infection of thecompound l-(p-chloro m nitrophenyl-diphenyl-methyl)- imidazole or apharmaceutically acceptable non-toxic salt thereof.

References Cited UNITED STATES PATENTS 3,321,366 5/1967 Mussell et al.424 273 JEROME D. GOLDBERG, Primary Examiner

